Case report eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):70-73 https://doi.org/10.12701/yujm.2020.00304 Co-existence of relapsing polychondritis and Crohn disease treated successfully with infliximab Hye-In Jung1, Hyun Jung Kim1, Ji-Min Kim2, Ju Yup Lee1, Kyung Sik Park1, Kwang Bum Cho1, Yoo Jin Lee1 1Division of Gastroenterology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea 2Division of Rheumatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea

Received: April 28, 2020 Revised: May 16, 2020 Relapsing polychondritis (RP) is a rare, progressive immune-mediated systemic inflammatory dis- Accepted: May 25, 2020 ease of unknown etiology, characterized by recurrent inflammation of cartilaginous structures. Approximately 30% of RP cases are associated with other autoimmune diseases. However, the Corresponding author: co-occurrence of RP and Crohn disease (CD) has rarely been reported. Herein, we present a Yoo Jin Lee 35-year-old woman diagnosed with RP and CD, who was refractory to initial conventional medi- Department of Internal Medicine, cations, including azathioprine and glucocorticoid, but who subsequently responded to infliximab Keimyung University School of (IFX). For both diseases, remission was sustained with IFX. There has been no previous report re- Medicine, 1035 Dalgubeol-daero, garding the successful treatment of co-existing RP and CD with IFX. Dalseo-gu, Daegu 42601, Korea Tel: +82-53-258-7739 Keywords: Crohn disease; Inflammatory bowel diseases; Infliximab; Relapsing polychondritis Fax: +82-53-258-4341 E-mail: [email protected]

Introduction 05-064). The patient provided written informed consent for pub- lication of clinical details and images. Relapsing polychondritis (RP) is a rare, immune-mediated A 35-year-old woman with polyarthralgia and intermittent fever multi-systemic disease characterized by inflammation of multiple for a 2-month duration was referred to our rheumatology clinic. cartilaginous tissues, particularly those in the ear, nose, tracheo- She presented with pain in multiple joints, including both hands, bronchial tree, and eye [1,2]. Although the pathogenesis of RP re- both wrists, right ankle, and both knees, and reported that the mains unclear, an immunological mechanism is considered to be pain was most prominent in both metacarpophalangeal and prox- crucial [1]. Accordingly, nearly 30% of RP reportedly coexists with imal interphalangeal joints. The patient was not on any medica- other autoimmune inflammatory disorders, including rheumatoid tion and had no prior illness. Laboratory tests revealed that C-re- arthritis, systemic lupus erythematosus, and Sjogren’s syndrome active protein was elevated to 6.32 mg/dL (range, 0–0.5 mg/dL), [3]. However, the co-occurrence of RP and Crohn disease (CD) is erythrocyte sedimentation rate was increased to 120 mm/hr rare, and the treatment strategy for such cases remains uncertain. (range, women < 25 mm/hr), hemoglobin was decreased to 10.4 Herein, we present a first report of co-existing RP and CD success- g/dL (range, 11–15 g/dL). Her rheumatoid factor was marginally fully treated with infliximab (IFX). elevated to 25.2 IU/mL (range, ≤ 20 IU/mL); however, anti-cy- clic citrullinated peptide antibody and antinuclear antibody were Case absent. All other biochemical parameters, leukocyte count, and electrolyte values were within normal limits. X-rays of multiple This study was approved by the Institutional Review Board of the joints were normal without evidence of erosion. Keimyung University Dongsan Hospital (IRB No: DSMC 2020- On physical examination, she presented bilateral injected con-

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70 https://doi.org/10.12701/yujm.2020.00304 Yeungnam Univ J Med 2021;38(1):70-73 junctiva (Fig. 1), as well as bilateral auricular redness and tender- the terminal ileum, cecum, and ascending colon, favoring a diag- ness, with sparing of the earlobes (Fig. 2). Ophthalmological ex- nosis of CD. Brownish, discolored colonic mucosa was observed, amination revealed bilateral episcleritis. An auricular biopsy was which was considered melanosis coli associated with the intake of performed, and various inflammatory cells were observed in the aloe vera (Fig. 4). Histological analyses of the colonoscopic biop- chondro-dermal junction (Fig. 3). Based on auricular cartilage in- sy revealed chronic inflammation. Her calprotectin level was flammation, ocular inflammation, and seronegative arthritis, she > 1,000 μg/g (range, < 50 μg/g). Collectively, the patient was fi- was diagnosed with RP according to the RP diagnostic criteria nally diagnosed with RP co-existing with CD. documented by Michet et al. [4]. After discontinuing NSAID therapy, she was treated with me- Initial treatment was started with a low-dose steroid (predniso- salazine (4 g/day), azathioprine (50 mg/day), and intravenous lone 10 mg) and non-steroidal anti-inflammatory drugs (IV) high-dose corticosteroid. With high-dose corticosteroid (NSAIDs) at the outpatient clinic. Three months later, she visited treatment, both CD- and RP-related symptoms were markedly the emergency department with fever, abdominal pain, and inter- improved. However, after tapering steroid treatment, she com- mittent hematochezia occurring for a month. A detailed interview plained of mild, fluctuating, but persisting abdominal pain, diar- focusing on gastrointestinal manifestations revealed that she had rhea, bilateral auricular pain, and polyarthritis. Despite mainte- been experiencing intermittent vague abdominal pain and diar- nance therapy comprising azathioprine and repeated steroid res- rhea 3–4 times per week for one year. She had self-diagnosed her cue therapy, flare-ups occurred twice in 6 months; thus, IV IFX (5 symptoms as irritable bowel syndrome and had often consumed mg/kg) was initiated. Following induction therapy with IFX, all aloe vera as a folk remedy. Interestingly, she reported that her ab- symptoms, including abdominal pain, diarrhea, auricular pain, dominal pain had repeatedly worsened, several times along with and arthralgia, were improved. Eighteen months after treatment the exacerbation of RP-related symptoms, such as arthralgia, con- with IFX, the colonoscopy showed that only ulcer scars and a few junctival injection, and bilateral auricular tenderness. Colonosco- inflammatory pseudopolyps remained. She had no RP recurrence py revealed multiple discontinuous ulcers with skipped lesions in and was confirmed to have reached not only a clinical but also an endoscopic remission with IFX.

Discussion

RP is a long-lasting, systemic inflammatory disease presenting di- verse clinical manifestations, with a flaring‒remitting course [3].

Fig. 1. Photo of patient's eye. Bilateral conjunctival injection is observed. Ophthalmologic examination presents corneal ulcer and iritis.

A B Fig. 3. Microscopic finding of auricular biopsy. The microscopic Fig. 2. Photos of both ears. The bilateral erythema of both finding of an auricular lesion shows perivascular infiltration auricles with sparing of the ear lobes (A, right; B, left) indicates of lymphocytes in a background of fibrous connective tissue bilateral auricular chondritis. (hematoxylin and eosin stain, ×200). https://doi.org/10.12701/yujm.2020.00304 71 Jung HI et al. Co-existence of relapsing polychondritis and Crohn disease

both wrists, right ankle, and both knees, with episcleritis and unique auricular chondritis appeared simultaneously, which con- curred with the criteria (B) of Michet et al. [4]. Although the etiology of RP remains unclear, an autoimmune RP hypothesis is supported owing to its frequent association with other autoimmune diseases, as well as the effectiveness of cortico- steroid and immunosuppressant treatments [2]. As both RP and A B IBD are immune-mediated diseases, they can theoretically appear together. Reportedly, RP has been introduced as one of the ex- tra-intestinal manifestations (EIMs) of IBD, but compared to oth- er EIMs, such as peripheral and axial arthropathies, erythema no- dosum, and pyoderma gangrenosum, RP is an extremely rare EIM of IBD [8,9]. Furthermore, RP is easily overlooked by clinicians, owing to its non-specific and unusual manifestations [2]. Howev- er, proper diagnosis and treatment of RP are essential, as it can C D cause severe functional complications, including deafness, loss of vision, balance disturbance, and airway obstruction [3,10]. Fig. 4. Colonoscopic findings. Multiple discontinuous ulcers are Owing to a lack of data, standardized RP treatment guidelines are present in the terminal ileum (A, B), cecum, and ascending colon yet to be established. Currently, the treatment strategy remains em- (C, D). Melanosis coli is observed probably due to the previous pirical, based on existing case reports. The treatment goal is symp- history of aloe vera consumption (C, D). tomatic control and the long-term inhibition of immune-mediated pathogenic mechanisms [1]. Thus, empirical tailored therapy, ac- cording to the severity of disease activity and organ involvement, As RP is an extremely rare disease, with an estimated prevalence has been provided [10]. Mild forms of RP with the involvement of a few cases per million [5], supporting data are extremely limit- of the external ear, nose, or joints are managed with NSAIDs, col- ed. To date, no specific laboratory or histological markers are chicine, dapsone, and low-dose corticosteroids, while severe RP available for RP, the diagnosis of RP is challenging and based on forms, with organ-threatening complications, require high-dose clinical findings [1]. The criteria suggested by Michet et al. [4] are corticosteroids [2]. Immunomodulators, such as azathioprine, the most commonly used for the diagnosis of RP and consist of methotrexate, and cyclosporine, have been used as steroid-sparing the following: (A) two or more major criteria (auricular chondri- therapy [1]. Although evidence is extremely limited, biologics tis, nasal chondritis, laryngotracheal chondritis), (B) one or more have been suggested as a secondary treatment for patients refrac- of the previously mentioned major and two or more minor crite- tory to conventional therapies. According to a review of reports ria (ocular inflammation, such as conjunctivitis, keratitis, episcleri- concerning RP treated with biologics, 62 patients with active RP tis, and uveitis; hearing loss; vestibular dysfunction; seronegative were treated with anti-tumor necrosis factor alpha (anti-TNFα) inflammatory arthritis). The most frequent clinical feature of RP agents; in 28, the treatment was effective, but six patients experi- is auricular chondritis, causing unilateral or bilateral inflammation enced only partial effects, and 28 reported no effect [11]. In the in the cartilage, with sparing of the earlobe. The second frequent IFX group, remission or partial remission was achieved in 18 of 31 manifestation is joint pain [2]. These findings were unequivocally patients [11]. demonstrated in our current case. Regarding polyarthritis, our Although a few cases regarding the co-existence of RP and IBD case differed from the clinical features of inflammatory bowel dis- have been documented, most have reported the co-existence of ease (IBD)-related spondyloarthritis. There are two types of RP and ulcerative colitis, with the co-occurrence of CD extremely IBD-related peripheral arthritis: oligoarticular and polyarticular rare. To date, we have found only one case report in English type [6]. The oligoarticular type involves less than five joints, pre- through a PubMed search in March 2020; this patient showed dominantly affecting the lower extremities. In contrast, the poly- resolution of RP with a mild form of CD after mesalazine treat- articular type involves more than five small joints (predominantly ment [12]. In our case, a 35-year-old woman with RP and CD had upper limbs), with symmetric distribution and unrelated with recurring symptoms, with flare-ups following conventional treat- IBD activity [6,7]. In this case, polyarthritis affecting both hands, ment but responded well to IFX therapy. Following IFX treat-

72 https://doi.org/10.12701/yujm.2020.00304 Yeungnam Univ J Med 2021;38(1):70-73 ment, both clinical and endoscopic remission was achieved and et al. Relapsing polychondritis: an update on pathogenesis, clin- RP-related symptoms improved. No previous report has de- ical features, diagnostic tools, and therapeutic perspectives. Curr scribed the successful treatment of co-existing RP and CD with Rheumatol Rep 2016;18:3. IFX. 3. Rednic S, Damian L, Talarico R, Scire CA, Tobias A, Costedo- In conclusion, clinicians should be aware that both RP and IBD at-Chalumeau N, et al. Relapsing polychondritis: state of the art can co-exist in patients. Additionally, anti-TNFα agents could be a on clinical practice guidelines. RMD Open 2018;4(Suppl treatment of choice for RP patients with IBD who are refractory 1):e000788. to conventional immunosuppressive therapy. 4. Michet CJ Jr, McKenna CH, Luthra HS, O’Fallon WM. Relaps- ing polychondritis: survival and predictive role of early disease Acknowledgments manifestations. Ann Intern Med 1986;104:74–8. 5. Horvath A, Pall N, Molnar K, Kovats T, Surjan G, Vicsek T, et Conflicts of interest al. A nationwide study of the epidemiology of relapsing poly- No potential conflict of interest relevant to this article was report- chondritis. Clin Epidemiol 2016;8:211–30. ed. 6. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropa- thies in inflammatory bowel disease: their articular distribution Author contributions and natural history. Gut 1998;42:387–91. Conceptualization: all authors; Formal analysis: JMK, JYL, KSP, 7. Rodriguez-Reyna TS, Martinez-Reyes C, Yamamoto-Furusho KBC, YJL; Methodology: HIJ, HJK, YJL; Investigation: HIJ, JK. Rheumatic manifestations of inflammatory bowel disease. HJK, YJL; Resources: HIJ, HJK, YJL; Supervision: JMK, JYL, World J Gastroenterol 2009;15:5517–24. KSP, KBC, YJL; Writing-original draft: HIJ, HJK, YJL; Writ- 8. Fousekis FS, Saridi M, Albani E, Daniel F, Katsanos KH, Kasta- ing-review & editing: all authors. nioudakis IG, et al. Ear involvement in inflammatory bowel dis- ease: a review of the literature. J Clin Med Res 2018;10:609–14. ORCID 9. Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Hye-In Jung, https://orcid.org/0000-0003-0047-9042 Rogler G. Extraintestinal manifestations of inflammatory bowel Hyun Jung Kim, https://orcid.org/0000-0001-6205-4897 disease. Inflamm Bowel Dis 2015;21:1982–92. Ji-Min Kim, https://orcid.org/0000-0002-3894-3413 10. Mathian A, Miyara M, Cohen-Aubart F, Haroche J, Hie M, Pha Ju Yup Lee, https://orcid.org/0000-0003-0021-5354 M, et al. Relapsing polychondritis: a 2016 update on clinical Kyung Sik Park, https://orcid.org/0000-0003-1874-9936 features, diagnostic tools, treatment and biological drug use. Kwang Bum Cho, https://orcid.org/0000-0003-2203-102X Best Pract Res Clin Rheumatol 2016;30:316–33. Yoo Jin Lee, https://orcid.org/0000-0003-1799-0146 11. Kemta Lekpa F, Kraus VB, Chevalier X. Biologics in relapsing polychondritis: a literature review. Semin Arthritis Rheum References 2012;41:712–9. 12. Touma DJ, Gross EJ, Karmody CS, Fawaz KA. Relapsing poly- 1. Borgia F, Giuffrida R, Guarneri F, Cannavo SP. Relapsing poly- chondritis in association with Crohn's disease. Am J Otolaryn- chondritis: an updated review. Biomedicines 2018;6:84. gol 1996;17:424–6. 2. Vitale A, Sota J, Rigante D, Lopalco G, Molinaro F, Messina M,

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